Agents acting at central cholecystokinin (CCK) receptors may induce satiety (Schick, Yaksh and Go, Regulatory Peptides 14:277-291, 1986). They are also expected to act as analgesics (Hill, Hughes and Pittaway, Neuropharmacology 26:289-300, 1987), and as anticonvulsants (MacVicar, Kerrin and Davison, Brain Research 406:130-135, 1987).
Reduced levels of CCK-peptides have been found in the brains of schizophrenic patients compared with controls (Roberts, Ferrier, Lee, Crow, Johnstone, Owens, Bacarese-Hamilton, McGregory, O'Shaughnessey, Polak and Bloom. Brain Research 288:199-211, 1983). It has been proposed that changes in the activity of CCK neurones projecting to the nucleus accumbens may play a role in schizophrenic processes by influencing dopaminergic function (Totterdell and Smith, Neuroscience 19:181-192, 1986). This is consistent with numerous reports that CCK peptides modulate dopaminergic function in the basal ganglia and particularly the nucleus accumbens (Weiss, Tanzer, and Ettenberg, Pharmacology, Biochemistry and Behaviour 30:309-317, 1988; Schneider, Allpert and Iversen, Peptides 4:749-753, 1983. It may therefore be expected that agents modifying CCK receptor activity may have therapeutic value in conditions associated with disturbed function of central dopaminergic function such as schizophrenia and Parkinson's disease.
CCK and gastrin peptides share a common carboxy terminal pentapeptide sequence and CCK peptides can bind to the gastrin receptor of the stomach mucosa and elicit acid secretion in many species including human (Konturek, Gastrointestinal Hormones, Ch. 23, pp 529-564, 1980, ed. G. B. J. Glass, Raven Press, N.Y.). Antagonists of the CCK-B receptor would also be expected to be antagonists at the stomach gastrin receptor and this would also be of value for conditions involving excessive acid secretion.
CCK and gastrin peptides have trophic effects on the pancreas and various tissues of the gastrointestional tract (Johnson, ibid., pp 507-527), actions which are associated with increased DNA and RNA synthesis. Moreover, gastrin secreting cells are associated with certain gastrointestinal tumors as in the Zollinger-Ellison syndrome (Stadil, ibid., pp 729-739), and some colorectal tumors may also be gastrin/CCK dependent (Singh, Walker, Townsend and Thompson, Cancer Research 46:1612, 1986, and Smith, J. P., Gastroenterology 95:1541, 1988). Antagonists of CCK/gastrin receptors could therefore be of therapeutic value as antitumor agents.
The CCK peptides are widely distributed in various organs of the body including the gastrointestinal tract, endocrine glands, and the nerves of the peripheral and central nervous systems. Various biologically active forms have been identified including a 33-amino acid hormone and various carboxyl-terminus fragments of this peptide (e.g., the octapeptide CCK26-33 and the tetrapeptide CCK30-33). (G. J. Dockray, Br. Med. Bull. 38(3):253-258, 1982).
The various CCK peptides are thought to be involved in the control of smooth muscle contractility, exocrine and endocrine gland secretion, sensory nerve transmission, and numerous brain functions. Administration of the native peptides cause gall bladder contraction, amylase secretion, excitation of central neurons, inhibition of feeding, anticonvulsive actions and other behavioral effects. ("Cholecystokinin: Isolation, Structure and Functions," G. B. J. Glass, Ed., Raven Press, New York, 1980, pp 169-221; J. E. Morley, Life Sciences 27:355-368, 1980; "Cholecystokinin in the Nervous System," J. de Belleroche and G. J. Dockray, Ed., Ellis Horwood, Chichester, England, 1984, pp 110-127.)
The high concentrations of CCK peptides in many brain areas also indicate major brain functions for these peptides (G. J. Dockray, Br. Med. Bull. 38(3):253-258, 1982). The most abundant form of brain CCK found is CCK26-33, although small quantities of CCK30-33 exist (Reheld and Gotterman, J. Neurochem. 32: 1339-1341, 1979). The role of central nervous system CCK is not known with certainty, but it has been implicated in the control of feeding (Dalla-Fera and Baile, Science 206:471-473, 1979).
Currently available appetite suppressant drugs either act peripherally, by increasing energy expenditure (such as thyroxine), or in some other manner (such as the biguanides), or act by exerting a central effect on appetite or satiety.
Centrally acting appetite suppressants either potentiate central catecholamine pathways and tend to be stimulants (for example, amphetamine), or influence serotonergic pathways (for example, fenfluramine). Other forms of drug therapy include bulking agents which act by filling the stomach, thereby inducing a "feeling" of satiety.
CCK is known to be present in some cortical interneurones which also contain gamma-aminobutyric acid (GABA) (H. Demeulemeester et al, J. Neuroscience 8:988-1000, 1988). Agents that modify GABA action may have utility as anxiolytic or hypnotic agents (S. C. Harvey, The Pharmacological Basis of Therapeutics (7th ed.) 1985, pp 399-371, MacMillan). Thus, agents which modify CCK action may have parallel anxiolytic or hypnotic activities. Aminoacyl-glycolic and -lactic esters are known as pro-drugs of amino acids (C. G. Wermuth, Chemistry and Industry, 433-435, 1980). Pro-drugs and soft drugs are known in the art (E. Palomino, Drugs of the Future 15(4) 361-368, 1990). The last two citations are hereby incorporated by reference.
The role of CCK in anxiety is disclosed in TIPS 11:271-273, 1990). Stella, V. J., et al, "Prodrugs", Drug Delivery Systems, pp. 112-176, 1985 and Drugs 29:455-73, 1985 disclose the concept of pro-drugs. J. Med. Chem. 33:344-347, 1990, disclosed pro-drug half esters. None of the foregoing references discloses pro-drugs of CCK antagonists.